Identification of new molecular targets and small molecule compounds to modulate saliva secretion for experimental treatment of salivary gland pathologies

Aim:

Hypo- and hypersalivation and resulting symptoms like xerostomia, dysphagia and aspiration hazard lead to a significant decrease in quality of life. Undernutrition and worsening of overall prognosis are common and, due to very limited treatment options, remain a significant challenge for treating doctors. Besides aging-related salivary dysfunctions, previous radiation, prescription drugs and rheumatologic disorders are common causes for salivary dysfunction. The chloride ion channel TMEM16A has been described as a key player of saliva secretion in mice. With current molecular assays and compound screening, we seek to identify new molecular drug targets and small molecule compounds that allow modulation of saliva production.

Methods:

Immunohistochemistry, RNA sequencing of human salivary gland/cell lines ex vivo/in vitro, compound screening (high-throughput).

Results:

Immunohistochemical stainings show TMEM16A expressed not only in human parotid (PG), but also in submandibular glands (SMG), in the secretory part. RNA sequencing of human PG and SMG biopsies and our HSaG-cell line confirmed TMEM16A expression and even revealed potentially new targets for modulation of saliva secretion. Compound screening using HSaG-cells was performed; several ones were identified that showed modulation of chloride secretion as a surrogate measure for saliva production in a dose-dependent manner.

Conclusion:

Our immunohistological and gene expression assays suggest that TMEM16A plays a key role in saliva proction also in human PG and SMG. The here-identified small molecules serve as a promising resource for further in vitro and vivo trials. Identification of additional ion channels as targets in salivary gland tissue might lead to future treatment options for therapy of salivary gland pathologies.

Publication History

Publication Date:
18 April 2018 (online)